Glutamate is the major excitatory neurotransmitter in the central nervous system, exerting its effects through both ionotropic and metabotropic glutamate receptors (mGlu receptors). The mGlu receptors are members of the family C G protein-coupled receptors (GPCRs), distinguished from other families of GPCRs by a large extracellular N-terminal agonist binding site (see Conn P J and Pin J P (1997) Pharmacology and functions of metabotropic glutamate receptors, Annu Rev Pharmacol Toxicol37:205-37 and Pin J P and Acher F (2002). The metabotropic glutamate receptors: structure, activation mechanism and pharmacology, Curr Drug Targets CNS Neurol Disord 1:297-317 for reviews). The mGlu receptors provide a mechanism by which glutamate can modulate or fine tune activity at the same synapses at which it elicits fast synaptic responses. There are eight known members of the mGlu family, divided into three groups based on sequence homology, pharmacology and coupling to intracellular signaling pathways. Group I mGlu receptors (mGlu I and mGluR5) are primarily localized at postsynaptic sites and couple to Gαq and increases in intracellular calcium. Group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, mGlu7 and mGlu8) mGlu receptors are predominantly localized presynaptically, and couple to Gαi/o and associated effectors such as inhibition of adenylyl cyclase and various ion channels.
The group I receptor mGluR5 has been implicated in a number normal physiological processes in the central nervous system (CNS) and previous studies suggest that selective agonists and antagonists of mGluR5 could have utility for treatment of a number of CNS disorders, including pain (Varney M A and Gereau R W (2002) Metabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics. Curr Drug Target CNS Neurol Disord 1 :283-96), anxiety disorders (Swanson C J, Bures M, Johnson M P, Linden A M, Monn J A and Schoepp D D (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4: 131-44. Spooren W and Gasparini F (2004) mGluR5 receptor antagonists: a novel class of anxiolytics? Drug News Perspect 17:251-7), Parkinson's disease (Marino M J and Conn J P (2002) Modulation of the basal ganglia by metabotropic glutamate receptors: potential for novel therapeutics. Curr Drug Target CNS Neurol Disord 1 :23950), addiction (Kenny P J and Markou A (2004) The ups and downs of addiction: role of metabotropic glutamate receptors. Trends Pharmacol Sci 25:265-72) and schizophrenia (Marino M J, Wittmann M, Bradley S R, Hubert G W, Smith Y and Conn P J (2001) Activation of group I metabotropic glutamate receptors produces a direct excitation and disinhibition of GABAergic projection neurons in the substantia nigra pars reticulata. J Neurosci 21:7001-12; Moghaddam B (2004) Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 174:39-44).
Unfortunately, it has been difficult to develop compounds that act as selective ligands at the orthosteric glutamate binding site of mGluR5 or other individual mGlu subtypes that have properties that are likely to be suitable for development of therapeutic agents.
It is an object of the invention to provide novel partial mGIuR5 antagonist compounds that do not suffer from disadvantageous side-effects, but which still offer therapeutic activity.